NM_004360.5:c.2077G>A (p.Gly693Ser) is a missense variant in CDH1 exon 13. Under the ClinGen CDH1 Expert Panel Specifications Version 3.1, no pathogenic or benign criteria are met. PVS1 is not applicable to missense variants. PM2 is not met because the variant exceeds the VCEP threshold of ≤1 per 100,000 alleles (gnomAD v2.1: ~4.2/100,000; v4.1: ~2.5/100,000). Population frequency is insufficient for BA1 (cutoff 0.2%) or BS1 (cutoff 0.1%). SpliceAI predicts no significant splicing impact (max delta 0.12), and PP3/BP4 are restricted to splicing predictors under the VCEP. No de novo, segregation, case-control, or functional data for this variant were identified among the four reviewed publications or ClinVar submissions. Multiple criteria are designated as Not Applicable by the CDH1 VCEP (PS1, PM1, PP2, PP4, BP1, PP5, BP6). The variant is classified as a Variant of Uncertain Significance.1
CDH1
Final classification
VUS
CDH1 c.2077G>A · p.Gly693Ser
CDH1
NM_004360.5:c.2077G>A (p.Gly693Ser) is a missense variant in CDH1 exon 13. Under the ClinGen CDH1 Expert Panel Specifications Version 3.1, no pathogenic or benign criteria are met. PVS1 is not applicable to missense variants. PM2 is not met because the variant exceeds the VCEP threshold of ≤1 per 100,000 alleles (gnomAD v2.1: ~4.2/100,000; v4.1: ~2.5/100,000). Population frequency is insufficient for BA1 (cutoff 0.2%) or BS1 (cutoff 0.1%). SpliceAI predicts no significant splicing impact (max delta 0.12), and PP3/BP4 are restricted to splicing predictors under the VCEP. No de novo, segregation, case-control, or functional data for this variant were identified among the four reviewed publications or ClinVar submissions. Multiple criteria are designated as Not Applicable by the CDH1 VCEP (PS1, PM1, PP2, PP4, BP1, PP5, BP6). The variant is classified as a Variant of Uncertain Significance.
ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1 v3.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
Classification rationale
VUS
CDH1 c.2077G>A
1
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗spliceai ↗cspec ↗pvs1_variant_assessmentrevelbayesdel
Gene diagram
· NM_004360.5 · variants mapped to exon structure
CDH1
NM_004360.5
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 14 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PVS1
PVS1 is not applicable to missense variants.
PS2
No de novo observation of NM_004360.5:c.2077G>A with parental confirmation meeting HDGC individual phenotype criteria has been identified in the reviewed literature or ClinVar submissions.
PS3
Under the CDH1 VCEP, PS3 can only be applied to demonstrate splicing defects via RNA assays.
PS4
No families meeting HDGC criteria and harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature.
PM2
Under the CDH1 VCEP, PM2_Supporting requires ≤1 allele per 100,000 in gnomAD.
PM6
No patients with NM_004360.5:c.2077G>A meeting HDGC individual phenotype criteria (without parental confirmation) have been identified in the reviewed literature.
PP1
No co-segregation data across informative meioses in families harboring NM_004360.5:c.2077G>A have been identified in the reviewed literature.
PP3
Under the CDH1 VCEP, PP3 is restricted to splicing predictions only (at least three in silico splicing predictors in agreement) and protein-based models are not to be used for missense variants.
Benign
BA1
The CDH1 VCEP BA1 allele frequency threshold is 0.2%.
BS1
The CDH1 VCEP BS1 allele frequency threshold is 0.1%.
BS2
The CDH1 VCEP requires observation in ≥3 individuals without gastric cancer, diffuse gastric cancer, signet ring cell tumors, or lobular breast cancer whose families do not suggest HDGC.
BS4
No segregation data are available for NM_004360.5:c.2077G>A to evaluate lack of segregation in affected family members.
BP2
No homozygotes for NM_004360.5:c.2077G>A are observed in gnomAD (0 homozygotes in both v2.1 and v4.1), and no data on observation in trans with a known pathogenic variant are available.
BP5
The CDH1 VCEP applies BP5 when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).
N/A · 11
PS1 · PM1 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47848e-05; MAF= 0.00248%, 40/1613890 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.79661e-05; MAF= 0.00280%, 33/1180002 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.24373e-05; MAF= 0.00424%, 12/282770 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.74257e-05; MAF= 0.00774%, 10/129156 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0025%
· 40 / 1,613,890
0 hom · FAF 0.002%
0 hom · FAF 0.002%
European (non-Finnish) 33 / 1,180,002 |
0.0028% |
African/African American 2 / 74,880 |
0.0027% |
East Asian 1 / 44,898 |
0.0022% |
South Asian 2 / 91,070 |
0.0022% |
Remaining individuals 1 / 62,488 |
0.0016% |
European (Finnish) 1 / 63,976 |
0.0016% |
+ 4 not observed (Admixed American, Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0042%
· 12 / 282,770
0 hom · FAF 0.0047%
0 hom · FAF 0.0047%
European (non-Finnish) 10 / 129,156 |
0.0077% |
African/African American 1 / 24,954 |
0.004% |
South Asian 1 / 30,616 |
0.0033% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 41785)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.042. BayesDel score = -0.7031.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDH1 (E-cadherin), a tumor suppressor involved in cell adhesion, is altered by mutation or deletion in various cancer typess, most frequently in breas
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 4 PMIDs not cited in assessment
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
22703879 ↗
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR